The goal of this proposal is to develop biomarkers for early identification of pulmonary vascular disease, such as pulmonary arterial hypertension (PAH). We propose to use non-invasive (and without contrast injection) proton magnetic resonance imaging (MRI) measures of lung density combined with arterial spin labeling measures of lung blood flow to calculate a measure of regional transit time -within a voxel (voxel transit time, VTT) and a proxy measure of local vascular resistance in humans and evaluate these as biomarkers of pulmonary vascular disease. In PAH, remodeling of distal blood vessels is largely silent and more than half of the pulmonary circulation must be obstructed before pulmonary arterial pressures rise -already very late in the pathological process. As vascular resistance increases, pulmonary transit time, the time for blood to traverse the pulmonary circulation, will be prolonged. There is evidence that patients with PAH mean transit time from the right heart to left heart is prolonged compared to normal subjects but there is considerable overlap between PAH patients and normals and thus mean transit time can not be used to identify early disease. Since the remodeling associated with PAH starts in the smaller, distal vessels, regional measures reflective of pulmonary transit time and pulmonary vascular resistance may provide greater sensitivity to detect changes. Our preliminary data shows that in patients with PAH the spatial distribution of VTT differs markedly from normals, suggesting that evaluating regional differences may provide increased sensitivity to early stages of pulmonary vascular disease. We propose to test the feasibility of this new approach by determining the reproducibility of the VTT metrics derived from density and blood flow and the sensitivity of these measures to detect physiologically meaningful changes. We will test the hypothesis that the healthy human pulmonary circulation exhibits distinctive distributions of VTT and estimated local vascular resistance and that these distributions are altered in a reproducible way by physiological challenges and differ in patients with established PAH. We will 1) evaluate the distributions of VTT and estimated local pulmonary vascular resistance of the healthy pulmonary circulation in repeated studies in normal subjects and how these are altered by hypoxia (FIO2=0.125) and exercise; 2) Quantify how VTT and estimated local pulmonary vascular resistance differs in patients with PAH in normoxia, and model the effect of assumptions used to derive them; 3) Use these characteristics to distinguish a fresh cohort of PAH patients from age and sex matched healthy controls (in a blinded fashion) and evaluate a cohort of patients with systemic sclerosis at very high risk of PAH. The potential high gain of this proposal is that successful completion of this project will provide a foundation for new ways of evaluating pulmonary vascular disease and may ultimately lead to a new screening tool for high-risk patient populations, by identifying altered regional characteristics of the pulmonary circulation. The techniques proposed here could be ultimately conducted on any 1.5 T clinical MRI scanner, increasing the potential use in routine screening.